Myocardial infarction (MI) is now among the most frequent causes of illness and death, especially in the industrial countries. If myocardial infarction is survived, the vitality of the patient is limited in most cases, by secondary symptoms such as paralysis or organ damage. There are also labor-intensive and cost-intensive follow-up treatments, such as convalescence, physiotherapy and medication to improve the health situation and prevent further complications.
Great advances have been made in recent years, especially in research into the causes of myocardial infarction, and these include cardiac tissue necrosis caused by an inadequate blood supply due to the occlusion of arterial blood vessels either by cholesterol plaque build-up, or by clot blockage (thrombosis). Risk factors for thrombosis-induced myocardial infarction are thought to include both hereditary and acquired conditions.
Generally, a tendency towards myocardial infarction could arise from hyperactive coagulation pathways, hypoactive anticoagulant mechanisms, or hypoactive fibrinolysis. Mutations in genes that encode proteins in these pathways are thought to play an important role in the predisposition to myocardial infarction.
The serine protease thrombin formed by cleavage of human prothrombin (also known as Factor II (FII)) exerts a central action to the processes of thrombosis and haemostasis. The thrombin molecule plays a role in the final stage of blood coagulation: the formation of an insoluble fibrin clot.
The hitherto known congenital disorders of prothrombin are rare and involve either reduced synthesis of the FII molecule (referred to as hypoprothrombinemia or type I prothrombin deficiency) or the normal synthesis of a dysfunctional molecule (referred to as dysprothrombinemia or type II prothrombin deficiency). Patients with dysprothrombinemia have only 2% to 50% of the clotting activity of normal prothrombin; in these patients the severity of the bleedings correlates fairly well with the amount of prothrombin activity in plasma. A number of dysprothrombinemias have been further characterized by amino acid sequence analysis of the isolated prothrombin molecule or by nucleotide sequence analysis of their prothrombin genes.
It is known that the gene variant Factor V Leiden (FVL-R506Q, or FVL) and prothrombin G20210A (FIIG20210A) are two of the most commonly recognized genetic prothrombic risk factors for venous thrombosis. Based on the increased thrombotic tendency in venous thrombosis studies, these two gene variants have also been examined for possible association with arterial thrombosis in myocardial infarction. The prothrombin variant G20210A, comprising a G to A transition mutation at nucleotide 20210 is a very good example. This point mutation is associated with increased prothrombin levels that lead to an increased risk of thrombosis (Poortn, Blood 1996; 88 (10): 3698-703). Publications indicate an increased risk of cardiac infarctions (Rosendahl, Blood 1997; 90(5) 1747-50) and venous thromboses (Brown, Br. J. Haematol; 98(4): 907-9). However, it has also been possible to demonstrate that discrimination between mutation carrier and the wild type is not possible on the basis of the prothrombin level, since the two groups cannot be separated (Poortn, Blood 1996; 88(10): 3698-703).
Several studies have shown higher prevalence of FIIG20210A in patients with myocardial infarction compared to normal controls. However, most of the results from these studies failed to achieve statistical significance, possible because of the extremely low frequency of FIIG20210A in the studied population and the use of relatively small sample sizes. Nevertheless, a few studies have presented conflicting results.
Although FVL strongly correlates with deep venous thrombosis, the majority of the previous studies have failed to show a correlation of FVL to myocardial infarction. Recently, a few studies have suggested that FVL may associate with early onset myocardial infarction and myocardial infarction with normal coronary angiography.
In contrast, a common gene variant, Factor XIIIV34L (FXIIIV34L) has recently been suggested to confer a protective role against myocardial infarction based on lower prevalence of FXIIIV34L in myocardial infarction patients compared with controls. However, conflicting results were also reported. Furthermore, results from function studies on the FXIIIV34L allele do not support the hypothesis of a protective role against myocardial infarction. Therefore, the role of these gene variants in the pathogenesis of myocardial infarction remains unknown.
Furthermore, no cause of myocardial infarction is detectable in a high proportion of all cases. If such defects exist, the hemostatic equilibrium is disturbed and the ratio between pro- and anticoagulatory factors is shifted in favor of one side. To this are added defects in the fibrinolysis system that reduce the breakdown of clots formed.
Being a multifactorial disorder, myocardial infarction may be a combined effect of a number of genes, with each playing only a small role. The predisposition imparted by individual genes may act independently or interact with other genes to result in an additive effect and/or a synergistic co-effect. Common challenges facing case control studies on possible gene-gene interactions include relatively small sample sizes, a low frequency of gene variants, and ethnic heterogeneity of the investigated population.
This background information is provided for the purpose of making known information believed by the applicant to be of possible relevance to the present invention. No admission is necessarily intended, nor should be construed, that any of the preceding information constitutes prior art against the present invention.